Comprehensive Protein Expression Analysis of Chronic Lymphocytic Leukemia Uncovers a Correlation of CDK4, P27 and P53 with Hierarchical Risk and Suggests a Dichotomy of Apoptosis and Proliferation.

Abstract 1255

Poster Board I-277

Chronic lymphocytic leukemia (CLL) has a variable clinical course. Genomic aberrations identify prognostic subgroups, pointing towards distinct underlying biological mechanisms. However, for a subset of aberrations, the affected cellular pathways are unknown. Even though the importance of posttranscriptional regulation, e.g. by micro RNAs, has become evident, the proteome of CLL remains little characterized. Therefore, the expression of 23 proteins involved in cell cycle, DNA damage, apoptosis and signaling was investigated in a total of 206 cytogenetically well characterized CLL cases by Western blotting. CLL cases were categorized according to the hierarchical model by Döhner et al. (NEJM 2000) into del(17p) (N=41), del(11q) (N=39), del(13q) (N=39) as sole abnormality, trisomy 12 (N=58) or normal karyotype (N=28). VH mutation status was available in 198 of 206 cases. For statistical analyses, protein expression was quantified by densitometry in 185 patients. Interestingly, in CLL subgroups with a good prognosis, differentially expressed proteins were rather involved in apoptosis. In contrast, in cytogenetic subgroups with a worse prognosis, deregulated proteins were associated with DNA damage and cell cycle control (see figure). In addition, higher levels of CDK4, P27 and P53 significantly correlated with increasing hierarchical risk as defined by genetic subgroups. Inter-protein correlations pointed to either STAT6-signaling or AKT1-signaling to be affected in CLL, but the low number of significant partial correlations between proteins underlines the major influence of genetic aberrations on the cellular CLL phenotype. In summary, differences in protein levels define distinct molecular phenotypes with a dichotomy of apoptosis and proliferation in CLL associated with prognostic subgroups. These findings open new therapeutic options for patient-tailored treatment of CLL.

Figure:

Overview of protein regulations in hierarchical subgroups of CLL suggesting a dichotomy of apoptosis and proliferation in CLL associated with benign and aggressive subgroups, respectively. The figure illustrates an increasing number of deregulated proteins associated with proliferation/DNA damage and a decreasing number of deregulated proteins that control apoptosis with higher genetic risk category (arrows indicate upregulation or downregulation when compared to other risk categories; two arrows: proteins with significant differential expression; single arrows: significant before adjustment for multiple testing (trend)).

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